The antibiotic doxorubicin (DXR) and its derivatives, as well as other cationic anthracyclines currently are of great clinical interest in the treatment of cancer, including leukemias and solid tumors.
Furthermore great hopes have centered around the use of liposomes as transport systems for bioactive agents. In these systems the drug is incorporated into the aqueous portion of the liposomes when it is hydrophilic or is distributed between the aqueous portion and the lipidic bilayers of the liposome when the drug shows a greater lipophilic nature. Once the drug is encapsulated, it can be administered to the patient to be treated.
It has been established by various investigators that the use of liposomes for the administration of antineoplastics in many cases improves the traditional methods of administration, see for example: Gabizon et al.: Cancer Res. (1982) 42, 4734-4739 and Van Hossel et al.: Cancer Res. (1984) 44, 3698-3705 (both herein incorporated by reference).
It has been observed by means of the utilization of various animal models that the encapsulation of doxorubicin in liposomes significantly reduces the secondary effects of toxicity, both chronic and acute. See, by way of example, Rahman et al.: Cancer Res. (1980) 40, 1532-1537, Forssen et al.: Proc. Natl. Acad. Sci. USA (1981) 78, 1873-1877, Olson et al.: Eur. J. Cancer Clin. Oncol. (1982) 18, 167-176, Rahman et al.: "Cancer" Res. (1985) 45, 796-803 and Gabizon et al.: J. Natl. Cancer Inst. (1986) 77, 459-467 (all herein incorporated by reference). Additionally, other indicators of toxicity, such as alopecia, loss of weight, nausea, vomiting, and also the dermal necrosis produced by extravasation may be reduced in significant manner by the administration of doxorubicin in liposomes. Forssen et al.: Cancer Treat. Rep. (1983) 67, 481-484,(herein incorporated by reference) see also the references cited previously in this paragraph.
Also, it has been established in various tumor models that this significant reduction of the toxicity is not produced at the expense of a reduction of the anti-tumor efficacy. Besides the references previously noted, see Rahman et al.: Chemoter, Pharmacol. (1986) 16, 22-27, Gabizon et al.: Cancer Res. (1983) 43, 4730-4735 and Br. J. Cancer (1985) 51, 681-689, Maythew et al.: J. Natl. Cancer Inst. (1987) 78, 707-713, Forssen et al.: Cancer Res. (1983) 43,546-550, and Storm et al.: Cancer Res. (1987) 47, 3366-3362 (all herein incorporated by reference).
The cardiomyopathy observed in treatments with doxorubicin is similar to the lesions seen in the cardiac muscles in experimental animals under conditions of alpha-tocopherol deficiency, Tomasz: Chem-Biol Interact. (1976) 13, 89. These results suggest that the lesions produced by the drug are caused by an increase in free-radical reactions in which lipids of membrane are seen to be involved. Therefore, the incorporation of doxorubicin, herein after DXR, into the lipidic bilayers of the liposomes may facilitate the unleashing of free-radical type reactions.
It has been observed that the incorporation of alpha-tocopherol in liposomes which contain DXR reduces the toxicity in animals and produces less cardiomyopathy than when combinations of alpha-tocopherol/DXR or liposomes/DXR in separate form are administered. Olson et al.: Eur. J. Clin. Oncol. (1982) 12(2). 167 (herein incorporated by reference). The reduction of toxicity achieved by means of the co-encapsulation of alpha-tocopherol and DXR in liposomes seems to result from a combination of the alteration in the biodistribution of the drug, due to the encapsulation of it in liposomes, and to a reduction of the damaging effect of the free radicals, due to the capture of these by the alpha-tocopherol.
Different patents describe the inclusion of anti-free radical agents into liposomes:
______________________________________ WO 85/00968, WO 85/04578, WO 87/02219 WO 87/04592 WO 88/09168 and EP 274 174 ______________________________________
(all herein incorporated by reference).
In most of the patents cited in general the presence of alpha-tocopherol is claimed, its salts and/or esters, even though other compounds like N-acetylcysteine, niacin, isocitrate or BHT have also been claimed.
Therefore, the search for compounds with improved activity as inhibitors of the lipid peroxidation is an active field of investigation. In this sense, a family of analogs of the Vitamin E with an excellent activity of elimination of free radicals has been described by Battoni et al.: Biochem. Biophys. Res. Commun. (1991) 174, 1103. In the same context in this patent the inhibiting activity of the lipidic peroxidation of compounds with structure of 2,2 dimethylchromenes and chromans is described, which are potentially applicable for stabilization of preparations in which anthracyclines in liposomes are incorporated, resulting in a notable reduction of the undesired effects of the drug.